Method for making amides

ABSTRACT

The invention relates to the manufacture of amide compounds provided through the reaction of nitrile compounds and a sulfate compound to form the related amide compound. In a preferred embodiment a diol or a triol is employed as a solvent, thereby increasing the yield of the product.

FIELD OF THE INVENTION

[0001] The present invention relates to amides, more specifically amethod of making butanamides in a new process.

BACKGROUND OF THE INVENTION

[0002] U.S. Pat. Nos. 4,153,679 and 4,226,988, hereby incorporated byreference, disclose the use of paramenthane and acyclic carboxamides ashaving a cooling effect on the skin and mucous membranes. These patentsdisclose the preparation and separation of the compounds through athree-step reaction sequence. The steps basically involve the hydrolysisof the compounds to an acid. The acid product is then reacted withthionyl chloride to form an acid chloride. The acid chloride is thenreacted with an alkylamine to form carboxy amide

[0003] While this reaction is suitable for preparing the carboxamides,the process does not lend itself to the manufacture of the desiredproduct in a simple economical process.

[0004] There is an ongoing need to provide the amides in high yield andin a simple, cost effective manner.

SUMMARY OF THE INVENTION

[0005] The invention a method for manufacturing amides of the formula

[0006] And where R is independently selected from hydrogen,(C₁-C₁₂)alkyl, (C₁-C₁₂)alkoxy, halo(C₁-C₁₂)alkyl, halo(C₁-C₁₂)alkoxy,(C₂-C₁₂)alkenyl, halo(C₂-C₁₂)alkenyl, (C₂-C₁₂)alkynyl,halo(C₂-C₁₂)alkynyl, (C₁-C₁₂)alkoxy(C₁-C₁₂)alkyl,(C₁-C₁₂)alkoxy(C₂-C₁₂)alkenyl, (C₁-C₁₂)alkoxy(C₂-C₁₂)alkynyl,(C₂-C₁₂)alkenyl(C₁-C₁₂)alkoxy, (C₂-C₁₂)alkynyl(C₁-C₁₂)alkoxy,(C₂-C₁₂)alkynyl(C₂-C₁₂)alkenyl, (C₂-C₁₂)alkenyl(C₂-C₁₂)alkynyl,(C₃-C₇)cycloalkyl, halo(C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₁₂)alkyl, (C₃-C₇)cycloalkyl(C₂-C₁₂)alkenyl,(C₃-C₇)cycloalkyl(C₂-C₁₂)alkynyl, (C₁-C₁₂) alkyl(C₃-C₇)cycloalkyl,(C₁-C₁₂)alkoxy(C₃-C₇)cycloalkyl, (C₂-C₁₂)alkenyl(C₃-C₇) cycloalkyl,(C₂-C₁₂)alkynyl(C₃-C₇)cycloalkyl, halo(C₁-C₁₂)alkyl(C₃-C₇)cycloalkyl,halo(C₁-C₁₂)alkoxy(C₃-C₇)cycloalkyl,halo(C₂-C₁₂)alkenyl(C₃-C₇)cycloalkyl,halo(C₂-C₁₂)alkynyl(C₃-C₇)cycloalkyl, halo(C₃-C₇)alkenyl(C₃-C₇)cycloalkyl, (C₁-C₁₂)alkoxy(C₁-C₁₂)alkyl(C₃-C₇)cycloalkyl,halo(C₃-C₇)cycloalkyl(C₃-C₇) cycloalkyl,(C₁-C₁₂)alkoxy(C₁-C₁₂)alkyl(C₃-C₇)cycloalkyl, (C₁-C₁₂)alkoxy(C₂-C₁₂)alkenyl(C₃-C₇) cycloalkyl,(C₂-C₁₂)alkenyl(C₁-C₁₂)alkoxy(C₃-C₇)cycloalkyl,(C₁-C₁₂)alkoxy(C₂-C₁₂)alkynyl(C₃-C₇) cycloalkyl,(C₂-C₁₂)alkynyl(C₁-C₁₂)alkoxy(C₃-C₇)cycloalkyl,(C₂-C₁₂)alkenyl(C₂-C₁₂)alkynyl(C₃-C₇)cycloalkyl,(C₂-C₁₂)alkynyl(C₂-C₁₂)alkenyl(C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₃-C₇) cylcoalkyl,(C₁-C₁₂)alkyl(C₃-C₇)cycloalkyl(C₃-C₇)cycloalkyl,(C₂-C₁₂)alkenyl(C₃-C₇)cycloalkyl(C₃-C₇)cycloalkyl,(C₂-C₁₂)alkynyl(C₃-C₇)cycloalkyl(C₃-C₇)cycloalkyl, (C₁-C₁₂)alkoxy(C₃-C₇)cycloalkyl(C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₁₂)alkyl(C₃-C₇)cycloalkyl, (C₃-C₇)cylcoalkyl(C₂-C₁₂)alkenyl(C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₂-C₁₂)alkynyl(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₁₂)alkoxy(C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₃-C₇)cycloalkyl(C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₁₂)alkenyl(C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₁₂)alkoxy(C₂-C₁₂) alkynyl(C₃-C₇)cycloalkyl, aryl,aralkyl, aryl(C₁-C₁₂)alkoxy, aryl(C₂-C₁₂)alkenyl, aryl(C₂-C₁₂) alkynyl,aryl(C₃-C₇)cycloalkyl, aryloxy(C₁-C₁₂)alkyl, aryloxy(C₂-C₁₂)alkynyl,aryloxy(C₂-C₁₂) alkenyl, aryl(C₁-C₁₂)alkoxy(C₃-C₇)cycloalkyl,aryl(C₂-C₁₂)alkenyl(C₃-C₇)cycloalkyl, aryl(C₂-C₁₂)alkynyl(C₃-C₇)cycloalkyl, aryl(C₃-C₇)cycloalkyl(C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkylaryl, aryl(C₁-C₄)alkyl(C₃-C₇)cycloalkyl, heterocyclic,aryl(C₁-C₄)alkylheterocyclic, aryl(C₂-C₄) alkenylheterocyclic,aryl(C₂-C₄)alkynylheterocyclic, heterocyclic (C₁-C₄)alkyl, andheterocyclic (C₃-C₇)cycloalkyl, (C₁-C₆)alkylphosphinyl,(C₁-C₆)alkylphosphonyl, (C₁-C₆)alkylphosphonate, (C₁-C₆)alkylphosphitecomprising:

[0007] Providing a nitrile compound of Formula II

[0008] and reacting the nitrile compound with the compound of FormulaIII hereinbelow:

[0009] where R is defined above

[0010] More specifically, the present invention is directed to thepreparation of N,2,3-trimethyl-2-isoethyl-menthylbutanamide by thereaction of dimethylsulfate and diisopropylpropionylnitrile. Anotherembodiment of the invention is directed to the preparation ofN-2,3-trimethyl-2-ethylbutanamide by the reaction of menthyl nitrilewith diethyl sulfate.

[0011] The present reaction provides yields of the amide in commerciallyacceptable yields, in a single reaction step. In a highly preferredembodiment, diol and triol esters are employed as a solvent which hasbeen found to increase reaction yields. These and other embodiments ofthe present invention will become apparent upon referring to thefollowing description of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0012] The present invention is based upon the discovery of a simple,efficient reaction to form the amide compounds recited herein. Thepreferred reaction products of the present invention areN-methyltrimethyl isopropyl butanamide and N-ethylmentyl carboxyamide.These amides are provided in a single reaction step by the reaction of anitrile compound and a sulfate compound.

[0013] Suitable nitrile materials of formula I includediisopropylpropionylnitrile, menthyl nitrile and the like.

[0014] The nitrites of Formula I are reacted with a sulfate compound offormula II, preferably selected from the group selected from dimethylsulfate and diethyl sulfate.

[0015] The compounds of Formula I and II can be added in stoichiometricequal amounts. Preferably the level of dimethyl sulfate or diethylsulfate is provided in stoichiometric excess so as to drive the reactionto higher yields of the resulting amide.

[0016] The aforementioned (C₁-C₁₂)alkyl, (C₁-C₁₂)alkoxy,(C₂-C₁₂)alkenyl, (C₂-C₁₂)alkynyl and (C₃-C₇)cycloalkyl groups may beoptionally substituted with up to three substituents selected from thegroup consisting of nitro, trihalomethyl and cyano.

[0017] The term “alkyl” includes both branched and straight chain alkylgroups from 1 to 12 carbon atoms. Typical alkyl groups are methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl,n-pentyl, isopentyl, n-hexyl, n-heptyl, isooctyl, nonyl, decyl, undecyl,dodecyl and the like. The term “haloalkyl” refers to an alkyl groupsubstituted with 1 to 3 halogens.

[0018] The term “alkoxy” includes both branched and straight chain alkylgroups from 1 to 12 carbon atoms containing at least one oxygen atom.Typical alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, sec-butoxy, isobutoxyl, t-butoxy, n-pentoxy, isopentoxy,n-hexoxy, n-heptoxy and the like. The term “haloalkoxy” refers to analkoxy group substituted with 1 to 3 halogens.

[0019] The term “alkenyl” refers to an ethylenically unsaturatedhydrocarbon group, straight or branched, having a chain length of 2 to12 carbon atoms and 1 to 2 ethylenic bonds. The term “haloalkenyl”refers to an alkenyl group substituted with 1 to 3 halogen atoms.

[0020] The term “alkynyl” refers to an unsaturated hydrocarbon group,straight or branched, having a chain length of 2 to 12 carbon atoms and1 to 2 acetylenic bonds. The term “halokynyl” refers to an alkynyl groupsubstituted with 1 to 3 halogens.

[0021] The term “cycloalkyl” refers to a saturated ring system having 3to 7 carbon atoms.

[0022] The term “aryl” includes phenyl or napthyl, which may besubstituted with up to three substituents independently selected fromthe group consisting of halogen, cyano, nitro, phenyl, phenoxy,(C₁-C₆)alkyl, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfoxide, (C₁-C₆)alkoxy,and halo (C₁-C₄) alkyl.

[0023] Typical aryl substituents include, but are not limited to,4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 2-methoxyphenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dibromophenyl,3,5-difluorophenyl, 2,4,6-trichlorophenyl, 4-methoxyphenyl,2-chloronapthyl, 2,4-dimethoxyphenyl, 4-(trifluoromethyl)phenyl and2-iodo-4-methylphenyl.

[0024] The term “heterocyclic” refers to a substituted or unsubstituted5 to 6 membered unsaturated ring containing one, two or threeheteroatoms, preferably one or two heteroatoms independently selectedfrom oxygen, nitrogen and sulfur, or to a bicyclic unsaturated ringsystem containing up to 10 atoms including one heteroatom selected fromoxygen, nitrogen and sulfur. Examples of heterocycles include, but arenot limited to, 2-, 3-, or 4-pyridinyl, pyrazinyl, 2-, 4-, or5-pyrimidinyl, pyridazinyl, triazolyl, imidazolyl, 2- or 3-thienyl, 2-or 3-furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, quinolyl and isoquinolyl. The heterocyclicring may be optionally substituted with up to two substituentsindependently selected from (C₁-C₂) alkyl, halogen, cyano, nitro andtrihalomethyl.

[0025] The term “aralkyl” is used to describe a group wherein the alkylchain is from 1 to 10 carbon atoms and can be branched or straightchain, preferably a straight chain, with the aryl portion, as definedabove, forming a terminal portion of the aralkyl moiety. Typical aralkylmoieties are optionally substituted benzyl, phenethyl, phenpropyl andphenbutyl moieties. Typical benzyl moieties are 2-chlorobenzyl,3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl,4-fluorobenzyl, 4-trifluoromethylbenzyl, 2,4-dichlorobenzyl,2,4-dibromobenzyl, 2-methylbenzyl, 3-methylbenzyl and 4-methylbenzyl.Typical phenethyl moieties are 2-(chlorophenyl)ethyl,2-(3-chlorophenyl)ethyl, 2-(4-chlorophenyl)ethyl,2-(2-fluorophenyl)ethyl, 2-(3-fluorophenyl)ethyl,2-(4-fluorophenyl)ethyl, 2-(2-methylphenyl)ethyl, 2-(3-phenyl)ethyl,2-(4-methylphenyl)ethyl, 2-(4-trifluoromethylphenyl)ethyl,2-(2methoxyphenyl)ethyl, 2-(3-methoxyphenyl) ethyl,2-(4-methoxyphenyl)ethyl, 2-(2,4-dichlorophenyl)ethyl,2-(3,5-dimethoxyphenyl)ethyl. Typical phenpropyl moieties are3-phenylpropyl, 3-(2-chlorophenyl)propyl, 3-(3-chlorophenyl)propyl,3-(4-chlorophenyl)propyl, 3-(2,4-dichlorophenyl)propyl,3-(2-fluorophenyl)propyl, 3-(3-fluorophenyl) propyl,3-(4-fluorophenyl)propyl, 3-(2-methylphenyl)propyl,3-(3-methylphenyl)propyl, 3-(4-methylphenyl)ethyl,3-(2-methoxyphenyl)propyl, 3-(3-methoxyphenyl)propyl,3-(4-methoxyphenyl) propyl, 3-(4-trifluoromethylphenyl)propyl,3-(2,4-dichlorophenyl)propyl and 3-3,5-dimethoxyphenyl) propyl.

[0026] Typical phenbutyl moieties include 4-phenylbutyl,4-(2-chlorophenyl)butyl, 4-(3-chlorophenyl) butyl,4-(4-chlorophenyl)butyl, 4-(2-fluorophenyl)butyl,4-(3-fluorophenyl)butyl, 4-(4-fluorophenyl) butyl,4-(2-methylphenyl)butyl, 4-(3-methylphenyl)butyl,4-(4-methylphenyl)butyl, 4-(2,4-dichlorophenyl)butyl,4-(2-methoxyphenyl)butyl, 4-(3-methoxyphenyl)butyl and4-(4-methoxyphenyl) butyl.

[0027] Halogen or halo is meant to include iodo, fluoro, bromo andchloro moieties.

[0028] The reaction temperature is from about 120 to about 165° C.;preferably from about 130 to about 155 and most preferably from 135 toabout 150° C.

[0029] In a preferred embodiment of the present invention, a solventsystem is employed. The Solvent is selected from various diol and triolesters and mixtures of these materials. The diol esters have thestructure of Formula IV

[0030] And triol esters of the structure presented in Formula V

[0031] Where R² is H or (C₁-C₁₈)alkyl; and R³ is H or (C₁-C₁₈)alkyl.

[0032] Suitable solvent materials include triacetin, propylene glycolacetate, ethylene glycol acetate, 1,2,6-hexanetriol acetate and thelike. Preferably the molar ratio of solvent to nitrile is greater thanabout 1.25/1; preferably greater than 1.5/1 and most preferably greaterthan 1.75/1. For example, a preferred the level of triacetin is 1.5times the stoichiometric level of diisopropylpropionitrile provided in areaction with dimethyl sulfate.

[0033] The present invention is sufficient to provide yields of greaterthan 50 mole % based upon the level of nitrile present. Yields ofgreater than about 60 mole percent and preferably greater that about 70mole percent are also possible with the present reaction.

[0034] It has surprisingly been found that the incorporation of themono, diol and triol esters as the solvent allows for higher yields andbetter reaction times. Reactions conducted without the diol or triolester solvent provided much lower yields and much longer reaction times.The invention will now be illustrated by the following example.

EXAMPLE 1 Preparation of Trimethyl Isopropyl Butanamide

[0035] Diisopropylproprionitrile (200 grams) and triacetin (1000 grams)were charged to a 5 liter reaction reactor equipped with a mechanicalstirrer, condenser, and heating mantle. The reactor contents are heatedto 145 C. Dimethyl sulfate (344 grams) is fed into the reactor whilerecovering methyl acetate. The batch is allowed to continue until nomore methyl acetate is recovered. The approximate reaction time wasabout 5 hours.

[0036] The contents of the reactor were then allowed to cool to roomtemperature and ethyl acetate is added to reduce the viscosity of theproduct. The batch is then decomped into 25% caustic. The crude iswashed twice with salt water. The crude is then distilled.

[0037] This procedure yielded approximately 70% mole/mole based on thecharged amount of diisopropylproprionitrile.

What is claimed is:
 1. A method for producing an amide of the formulaThe invention a method for manufacturing amides of the formula

Comprising reacting a nitrile of Formula II

and reacting said compound with a compound of Formula III.

where R is defined above independently selected from hydrogen,(C₁-C₁₂)alkyl, (C₁-C₁₂)alkoxy, halo(C₁-C₁₂)alkyl, halo(C₁-C₁₂)alkoxy,(C₂-C₁₂)alkenyl, halo(C₂-C₁₂)alkenyl, (C₂-C₁₂)alkynyl,halo(C₂-C₁₂)alkynyl, (C₁-C₁₂)alkoxy(C₁-C₁₂)alkyl,(C₁-C₁₂)alkoxy(C₂-C₁₂)alkenyl, (C₁-C₁₂)alkoxy(C₂-C₁₂)alkynyl,(C₂-C₁₂)alkenyl(C₁-C₁₂)alkoxy, (C₂-C₁₂)alkynyl(C₁-C₁₂)alkoxy,(C₂-C₁₂)alkynyl(C₂-C₁₂)alkenyl, (C₂-C₁₂)alkenyl(C₂-C₁₂)alkynyl,(C₃-C₇)cycloalkyl, halo(C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₁₂)alkyl, (C₃-C₇)cycloalkyl(C₂-C₁₂)alkenyl,(C₃-C₇)cycloalkyl(C₂-C₁₂)alkynyl, (C₁-C₁₂) alkyl(C₃-C₇)cycloalkyl,(C₁-C₁₂)alkoxy(C₃-C₇)cycloalkyl, (C₂-C₁₂)alkenyl(C₃-C₇) cycloalkyl,(C₂-C₁₂)alkynyl(C₃-C₇)cycloalkyl, halo(C₁-C₁₂)alkyl(C₃-C₇)cycloalkyl,halo(C₁-C₁₂)alkoxy(C₃-C₇)cycloalkyl,halo(C₂-C₁₂)alkenyl(C₃-C₇)cycloalkyl,halo(C₂-C₁₂)alkynyl(C₃-C₇)cycloalkyl, halo(C₃-C₇)alkenyl(C₃-C₇)cycloalkyl, (C₁-C₁₂)alkoxy(C₁-C₁₂)alkyl(C₃-C₇)cycloalkyl,halo(C₃-C₇)cycloalkyl(C₃-C₇) cycloalkyl,(C₁-C₁₂)alkoxy(C₁-C₁₂)alkyl(C₃-C₇)cycloalkyl, (C₁-C₁₂)alkoxy(C₂-C₁₂)alkenyl(C₃-C₇) cycloalkyl,(C₂-C₁₂)alkenyl(C₁-C₁₂)alkoxy(C₃-C₇)cycloalkyl,(C₁-C₁₂)alkoxy(C₂-C₁₂)alkynyl(C₃-C₇) cycloalkyl,(C₂-C₁₂)alkynyl(C₁-C₁₂)alkoxy(C₃-C₇)cycloalkyl,(C₂-C₁₂)alkenyl(C₂-C₁₂)alkynyl(C₃-C₇)cycloalkyl,(C₂-C₁₂)alkynyl(C₂-C₁₂)alkenyl(C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₃-C₇) cylcoalkyl,(C₁-C₁₂)alkyl(C₃-C₇)cycloalkyl(C₃-C₇)cycloalkyl,(C₂-C₁₂)alkenyl(C₃-C₇)cycloalkyl(C₃-C₇)cycloalkyl,(C₂-C₁₂)alkynyl(C₃-C₇)cycloalkyl(C₃-C₇)cycloalkyl, (C₁-C₁₂)alkoxy(C₃-C₇)cycloalkyl(C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₁₂)alkyl(C₃-C₇)cycloalkyl, (C₃-C₇)cylcoalkyl(C₂-C₁₂)alkenyl(C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₂-C₁₂)alkynyl(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₁₂)alkoxy(C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₃-C₇)cycloalkyl(C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₁₂)alkenyl(C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₁₂)alkoxy(C₂-C₁₂) alkynyl(C₃-C₇)cycloalkyl, aryl,aralkyl, aryl(C₁-C₁₂)alkoxy, aryl(C₂-C₁₂)alkenyl, aryl(C₂-C₁₂) alkynyl,aryl(C₃-C₇)cycloalkyl, aryloxy(C₁-C₁₂)alkyl, aryloxy(C₂-C₁₂)alkynyl,aryloxy(C₂-C₁₂) alkenyl, aryl(C₁-C₁₂)alkoxy(C₃-C₇)cycloalkyl,aryl(C₂-C₁₂)alkenyl(C₃-C₇)cycloalkyl, aryl(C₂-C₁₂)alkynyl(C₃-C₇)cycloalkyl, aryl(C₃-C₇)cycloalkyl(C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkylaryl, aryl(C₁-C₄)alkyl(C₃-C₇)cycloalkyl, heterocyclic,aryl(C₁-C₄)alkylheterocyclic, aryl(C₂-C₄) alkenylheterocyclic,aryl(C₂-C₄)alkynylheterocyclic, heterocyclic (C₁-C₄)alkyl, andheterocyclic (C₃-C₇)cycloalkyl, (C₁-C₆)alkylphosphinyl,(C₁-C₆)alkylphosphonyl, (C₁-C₆)alkylphosphonate, (C₁-C₆)alkylphosphite.2. The method of claim 1 wherein a solvent is employed.
 3. The method ofclaim 2 wherein the solvent is selected from diol esters, triol estersand mixtures thereof.
 4. The method of claim 3 wherein the solvent isselected from a diol ester has a structure of Formula IV:

And triols of the structure presented in Formula V

where R₂ is selected from H and (C₁-C₁₅)alkyl; and R₃ is selected from Hand (C₁-C₁₈)alkyl.
 5. The method of claim 1 wherein the sulfate isdimethyl sulfate.
 6. The method of claim 6 wherein the nitrile isdiisoprpionylnitrile.
 7. The method of claim 6 wherein the amide istrimethylisopropylbutanamide.
 8. The method of claim 1 wherein the yieldis greater than about 50 mole percent.
 9. The method of claim 4 whereinthe solvent is selected from the group consisting of triacetin,propylene glycol acetate, ethylene glycol acetate, and 1,2,6-hexanetriolacetate.
 10. The method of claim 1 wherein Q is selected from the groupconsisting of